Osteoblastic regulation of B lymphopoiesis is mediated by Gs{alpha}-dependent signaling pathways.
Osteoblasts play an increasingly recognized role in supporting hematopoietic development and recently have been implicated in the regulation of B lymphopoiesis. Here we demonstrate that the heterotrimeric G protein alpha subunit G(s)alpha is required in cells of the osteoblast lineage for normal postnatal B lymphocyte production. Deletion of G(s)alpha early in the osteoblast lineage results in a 59% decrease in the percentage of B cell precursors in the bone marrow. Analysis of peripheral blood from mutant mice revealed a 67% decrease in the number of circulating B lymphocytes by 10 days of age. Strikingly, other mature hematopoietic lineages are not decreased significantly. Mice lacking G(s)alpha in cells of the osteoblast lineage exhibit a reduction in pro-B and pre-B cells. Furthermore, interleukin (IL)-7 expression is attenuated in G(s)alpha-deficient osteoblasts, and exogenous IL-7 is able to restore B cell precursor populations in the bone marrow of mutant mice. Finally, the defect in B lymphopoiesis can be rescued by transplantation into a WT microenvironment. These findings confirm that osteoblasts are an important component of the B lymphocyte niche and demonstrate in vivo that G(s)alpha-dependent signaling pathways in cells of the osteoblast lineage extrinsically regulate bone marrow B lymphopoiesis, at least partially in an IL-7-dependent manner.
Wu
Joy Y
JY
Endocrine Unit and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Purton
Louise E
LE
Rodda
Stephen J
SJ
Chen
Min
M
Weinstein
Lee S
LS
McMahon
Andrew P
AP
Scadden
David T
DT
Kronenberg
Henry M
HM
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D015851:Interleukin-7; D019205:GTP-Binding Protein alpha Subunits, Gs